Cyclin-Dependent Kinase Regulation during G1 Phase and Cell Cycle Regulation by TGF-ß

This chapter provides insight into the molecular mechanisms by which transforming growth factor-β (TGF-β) modulates cell cycle progression in different cell types. Particular attention is focused on the differences between the mechanisms in cells of epithelial origin and in mesenchymally derived cells. The role of cyclin-dependent kinases (cdks) in the mammalian cell cycle is discussed. The chapter examines how cdk activity is modulated by cyclin binding, phosphorylation, and ckis, including the Ink4 proteins and the closely related inhibitors p2lCip1 and p27kip1. Particular attention is paid to the role of p27Kip1 and p2lCip1 in the mechanism of TGF-β-induced suppression or stimulation of the cell cycle and how these mechanisms contrast between epithelial cells and cells of mesenchymal origin. Other aspects of TGF-β signal transduction are discussed, including its effects on cyclin and cdk expression in various cell types and the downstream targets of cdks and their modulation by TGF-β and other growth factors are also discussed. These include proteins of the retinoblastoma family, and the related modulation of the transcriptional activity of the E2F family members. Finally, the role of cell cycle regulatory proteins in oncogenesis is reviewed.